As children we need to learn an infinite set of skills. Our brain, the site where all information converges and is processed, shapes and is shaped by our perception. Synapses transfer environmental inputs to neurons and the integration of these signals determines the neuronal response to a specific stimulus (Huberman et al., 2006; Mrsic-Flogel et al., 2006). Neural plasticity modulates the strength of synapses when they are activated by relevant inputs. Plasticity is particularly important during brain development when periods of intense refinement of neural circuits - critical periods - lead to a mature and healthy functioning brain (Hubel and Wiesel, 1970; Katz and Shatz, 1996; Morales et al., 2002; Hensch, 2005). In primary visual cortex, one of the best studied models for experience-dependent plasticity, synapse specific forms of plasticity such as long term potentiation (LTP) or depression (LTD) are fundamental mechanisms for visual neuron function (Smith et al., 2009). The central role of inhibitory synaptic transmission in cortical circuits is demonstrated by the involvement of inhibitory synapses in the modulation of the onset and duration of critical periods (Hensch et al., 1998; Fagiolini and Hensch, 2000; Fagiolini et al., 2004). Inhibitory synaptic transmission mediated by fast spiking interneurons (FS) is directly affected by experience (Maffei et al., 2004; Maffei et al., 2006). A novel form of plasticity - LTP of FS to pyramidal neuron synapses, LTPi - is induced in layer 4 by changes in visual drive. LTPi might contribute to shaping visual cortical neurons responsiveness and receptive fields; but if induced at maximal, or saturating, levels, such as those measured after visual deprivation, it might promote loss of function (Maffei et al., 2006). LTPi induction properties are the subject of the present proposal. State of the art electrophysiological techniques will be used to dissect the mechanisms for induction of LTPi. More specifically we will determine 1) the dependence of LTPi induction on the timing of FS and pyramidal neuron activity; 2) LTPi requirement for coincidence detection mechanisms; 3) its dependence on the range of postsynaptic neuron activity - subthreshold vs. suprathreshold; 4) LTPi dependence on presynaptic frequency of firing. We will also begin to investigate the cellular mechanisms for LTPi: the dependence on calcium influx and the intracellular pathways involved in GABAA receptor trafficking at synapses- PKA (Poisbeau et al., 1999) - and in the regulation of GABAA receptor function - PKC (Poisbeau et al., 1999; Brandon et al., 2000; Song and Messing, 2005). Quadruple concurrent patch clamp recordings will be obtained from pyramidal and FS to measure the strength, dynamics and plasticity of monosynaptic inhibitory connections. Specific drugs will be applied to prevent the induction of LTPi and to begin the identification of the cellular pathways involved in its induction. PUBLIC HEALTH RELEVANCE: Visual experience shapes cortical circuits during development. Synapses translate environmental inputs into signals that are integrated by neurons, which, in turn, produce appropriate responses to the sensory stimulus (Huberman et al., 2006; Mrsic-Flogel et al., 2006). The central role played by inhibitory synaptic transmission in visual cortical circuits is demonstrated by recent findings regarding inhibitory synapses and the modulation of the onset and duration of critical periods for plasticity (Hensch et al., 1998; Hensch, 2005). The maturation and plasticity of inhibitory synapses in visual cortex are essential for the processing of visual inputs and the preservation of balanced circuit excitability (Rozas et al., 2001; Morales et al., 2002; Hensch and Fagiolini, 2005).